Hookworms infect nearly one billion people worldwide and are a leading cause of anemia and malnutrition in resource limited countries. Current global strategies to control hookworm and other Soil Transmitted Helminths rely on repeated Mass Drug Administration of benzimidazole anthelminthics, most commonly albendazole. Recent evidence confirms that deworming drugs are losing effectiveness against hookworm in endemic areas, and the emergence of genetically mediated resistance would have potentially devastating public health implications. The Ghana-Yale Partnership for Global Health has conducted field based studies across 13 communities within the Kintampo North Municipality (KNM) of central Ghana. Studies in adults and school age children (2007-2015) confirm the overall poor efficacy of albendazole, and have identified at least one community in Kintampo where treatment was associated with a 0% cure rate and sub-standard reduction in fecal egg excretion. Based on these preliminary data, we hypothesize that the mechanism of hookworm treatment failure in Kintampo involves genetically mediated resistance to albendazole. In order to test this hypothesis, we propose two specific aims. In Specific Aim 1, a national Anthelminthic Response Map (AR-Map) for Ghana will be defined across the country's 10 regions, in order to identify communities at high risk for benzimidazole resistance. Field isolates will be collected and genomic DNA interrogated to define genotypic variation and identify resistance markers using deep sequencing techniques. In Specific Aim 2, high sensitivity molecular diagnostics will be developed and field tested, with the goal of screening communities exposed to MDA for long term impact and emerging resistance. Over the course of the 5 year study period, this TMRC project will support collaborative research and training to build capacity in parasitic diseases research, building on the longstanding record of the Ghana-Yale Partnership for Global Health. Ultimately, development of molecular methods to elucidate the mechanisms of treatment failure will bridge a pressing technological gap and fill a critical public health need in Ghana and other resource limited countries.